37 research outputs found
Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study
BACKGROUND: Only few data are available on treatment-associated behavior of distinct rare CNS-embryonal tumor entities previously treated as "CNS-primitive neuroectodermal tumors" (CNS-PNET). Respective data on specific entities, including CNS neuroblastoma, FOXR2 activated (CNS NB-FOXR2), and embryonal tumor with multi-layered rosettes (ETMR) are needed for development of differentiated treatment strategies. METHODS: Within this retrospective, international study, tumor samples of clinically well-annotated patients with the original diagnosis of CNS-PNET were analyzed using DNA methylation arrays (n=307). Additional cases (n=66) with DNA methylation pattern of CNS NB-FOXR2 were included irrespective of initial histological diagnosis. Pooled clinical data (n=292) were descriptively analyzed. RESULTS: DNA methylation profiling of "CNS-PNET" classified 58(19%) cases as ETMR, 57(19%) as HGG, 36(12%) as CNS NB-FOXR2, and 89(29%) cases were classified into 18 other entities. Sixty-seven (22%) cases did not show DNA methylation patterns similar to established CNS tumor reference classes. Best treatment results were achieved for CNS NB-FOXR2 patients (5-year PFS: 63%±7%, OS: 85%±5%, n=63), with 35/42 progression-free survivors after upfront craniospinal irradiation (CSI) and chemotherapy. The worst outcome was seen for ETMR and HGG patients with 5-year PFS of 18%±6% and 22%±7%, and 5-year OS of 24%±6% and 25%±7%, respectively. CONCLUSION: The historically reported poor outcome of CNS-PNET patients becomes highly variable when tumors are molecularly classified based on DNA methylation profiling. Patients with CNS NB-FOXR2 responded well to current treatments and a standard-risk-CSI based regimen may be prospectively evaluated. The poor outcome of ETMR across applied treatment strategies substantiates the necessity for evaluation of novel treatments
Diagnosis and treatment of thyroid cancer in children in the multicenter analysis in Poland for PPGGL
Introduction: Differentiated thyroid carcinoma (DTC) in
children presents different biological behavior in comparison
to adults. Authors presents preliminary results of multicenter
analysis concerning incidence, diagnostics and treatment
of DTC in children.
Material and methods: The study is a retrospective analysis
of 107 pediatric patients from 14 academic centers based
on the data from 2000 to 2005 obtained by questionnaire in
hospitals involved in the treatment of DTC in children.
Results: Papillary thyroid cancer was diagnosed in 83 children,
follicular thyroid cancer in 10 children and medullary
thyroid cancer in 14 children. Incidence of DTC in children
was estimated between 18 and 23 cases per year. The biggest
group of patients consisted of children between 11 and
15 years of age, with girls to boys ratio 3.3 : 1. Clinically DTC
in children presented most often as solitary thyroid nodule.
Cervical lymphadenopathy was observed in 42% of patients.
Intraoperative verification indicated metastatic nodes
in 50% of children. Low stage DTC predominated (T1
in 36% and T2 in 26% of children). One step surgery was performed in 65% of children with DTC, two step surgery
in 25% of patients. I131 therapy was undertaken in 80% of
children. Lung metastases were indicated in post therapeutic
studies in 14% of children with DTC. Prophylactic thyroidectomies
were performed in 79% of children in the group
of patients with MTC and RET gene mutations.
Conclusions: The necessity of introduction of unified therapeutic
standard in children with DTC in Poland is underlined.Wstęp: Zróżnicowane raki tarczycy (DTC, differentiated thyroid
carcinoma) występują u dzieci rzadko. Większość przypadków
wykrywanych jest w wieku 11-17 lat. W odróżnieniu
od dorosłych DTC u dzieci prezentują odmienne zachowanie
biologiczne. Mała liczba przypadków DTC
w poszczególnych ośrodkach oraz względnie łagodny ich
przebieg utrudniają ocenę występowania i leczenia DTC
u dzieci w Polsce, uzależniając ją od wysiłków włożonych
w uzyskanie rzetelnych danych. Autorzy przedstawiają
wstępne wyniki analizy wieloośrodkowej dotyczące występowania,
diagnostyki i leczenia DTC u dzieci.
Materiał i metody: Podjęte badania są retrospektywną analizą
obejmującą lata 2000-2005, opartą na danych z historii
chorób uzyskanych z ankiet rozesłanych do ośrodków dla
dzieci i dorosłych podejmujących leczenie DTC. Do analizy
zgłoszono 107 pacjentów z 14 ośrodków akademickich
w Polsce. Analizie poddano wiek i płeć dzieci z DTC, wielkość
i lokalizację zmian w tarczycy, sposoby rozpoznawania
DTC, rodzaje i zakres wykonywanych zabiegów operacyjnych
oraz leczenie uzupełniające izotopem J131.
Wyniki: Raka brodawkowatego stwierdzono u 83 dzieci,
pęcherzykowego u 10 dzieci, a rdzeniastego u 14 dzieci. Częstość
występowania DTC u dzieci w Polsce wahała się między
18 a 23 przypadkami rocznie. W województwach: mazowieckim
i połączonych wielkopolskim i lubuskim wykazano
w okresie 2000-2005 wyższą (24 i 25) częstość występowania
DTC, w pozostałych województwach wykazywano
od 2 do 10 przypadków DTC. Największą grupę pacjentów
stanowiły dzieci w wieku 11-15 lat, a stosunek dziewcząt do chłopców wynosił 3,3 : 1. Klinicznie DTC prezentowały
się najczęściej jako pojedyncze guzki tarczycy. Limfadenopatię
szyjną w badaniu klinicznym stwierdzono
u 42% pacjentów, a śródoperacyjnie u 50% dzieci. U większości
pacjentów dominowały niższe stopnie zaawansowania
DTC (T1 u 36% i T2 u 26% dzieci). Operacje jednoetapowe
wykonano u 65% dzieci, operacje dwuetapowe u 25%
dzieci, a profilaktyczne tyreoidektomie u 79% dzieci z grupy
pacjentów z rakiem rdzeniastym tarczycy (MTC, medullary
thyroid cancinoma) i mutacją genu Ret. Leczenie izotopowe
J131 podjęto u 80% dzieci. Przerzuty do płuc w scyntygrafii
poterapeutycznej wykazano u 14% dzieci z DTC.
Wnioski: We wnioskach podkreśla się konieczność wdrożenia
na terenie całego kraju ujednoliconego i ocenianego
na podstawie obiektywnych przesłanek sposobu postępowania
z dziećmi z DTC
Development of the SIOPE DIPG network, registry and imaging repository : a collaborative effort to optimize research into a rare and lethal disease
Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6-6.4 months) and the median overall survival is 11.0 months (95% CI 10.5-11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG.Peer reviewe
Efficacy and safety of Everolimus in children with TSC - associated epilepsy – Pilot data from an open single-center prospective study
TERT promoter mutations are highly recurrent in SHH subgroup medulloblastoma
Telomerase reverse transcriptase (TERT) promoter mutations were recently shown to drive telomerase activity in various cancer types, including medulloblastoma. However, the clinical and biological implications of TERT mutations in medulloblastoma have not been described. Hence, we sought to describe these mutations and their impact in a subgroup-specific manner. We analyzed the TERT promoter by direct sequencing and genotyping in 466 medulloblastomas. The mutational distributions were determined according to subgroup affiliation, demographics, and clinical, prognostic, and molecular features. Integrated genomics approaches were used to identify specific somatic copy number alterations in TERT promoter-mutated and wild-type tumors. Overall, TERT promoter mutations were identified in 21 % of medulloblastomas. Strikingly, the highest frequencies of TERT mutations were observed in SHH (83 %; 55/66) and WNT (31 %; 4/13) medulloblastomas derived from adult patients. Group 3 and Group 4 harbored this alteration in <5 % of cases and showed no association wit
Cytogenetic Prognostication Within Medulloblastoma Subgroups
PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials
Same-Sex Marriage and the Boundaries of Diversity: Will Marriage and Family Therapy Remain Inclusive of Religious and Social Conservatives?
Subgroup-specific structural variation across 1,000 medulloblastoma genomes.
Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy
Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease
Diffuse intrinsic pontine glioma (DIPG) is a rare and deadly childhood malignancy. After 40 years of mostly single-center, often non-randomized trials with variable patient inclusions, there has been no improvement in survival. It is therefore time for international collaboration in DIPG research, to provide new hope for children, parents and medical professionals fighting DIPG. In a first step towards collaboration, in 2011, a network of biologists and clinicians working in the field of DIPG was established within the European Society for Paediatric Oncology (SIOPE) Brain Tumour Group: the SIOPE DIPG Network. By bringing together biomedical professionals and parents as patient representatives, several collaborative DIPG-related projects have been realized. With help from experts in the fields of information technology, and legal advisors, an international, web-based comprehensive database was developed, The SIOPE DIPG Registry and Imaging Repository, to centrally collect data of DIPG patients. As for April 2016, clinical data as well as MR-scans of 694 patients have been entered into the SIOPE DIPG Registry/Imaging Repository. The median progression free survival is 6.0 months (95% Confidence Interval (CI) 5.6–6.4 months) and the median overall survival is 11.0 months (95% CI 10.5–11.5 months). At two and five years post-diagnosis, 10 and 2% of patients are alive, respectively. The establishment of the SIOPE DIPG Network and SIOPE DIPG Registry means a paradigm shift towards collaborative research into DIPG. This is seen as an essential first step towards understanding the disease, improving care and (ultimately) cure for children with DIPG. © 2017, The Author(s)